Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are released from the anterior pituitary gland under the control of the releasing hormone LH-RH produced in the hypothalamic region. LH and FSH act on the gonads to stimulate the synthesis of steroid hormones and to stimulate gamete maturation. The pulsatile release of LH-RH, and thereby the release of LH and FSH, controls the reproductive cycle in domestic animals and humans. Additionally, LH-RH has effects in placenta, in releasing HCG, and directly on the gonads. Agonist analogs of LH-RH are useful for the control of fertility by two mechanisms of action. Low doses of LH-RH analogs can stimulate ovulation and are useful in the treatment of hypothalamic and ovulatory infertility. Additionally they can be used for hypogonadal conditions and impotence, and stimulate spermatogenesis and androgen production in the male. Paradoxically, larger doses of highly potent and long-lasting analogues of LH-RH have an opposite effect and block ovulation in the female and suppress spermatogenesis in the male. Related to these effects is a suppression of normal circulating levels of sexual steroids of gonadal origin, resulting in reduction in accessory organ weight in the male and the female. In domestic animals this paradoxical effect promotes weight gain in a feed-lot situation, stimulates abortion in pregnant animals and in general, acts as a chemical sterilant.
The natural hormone releasing hormone LH-RH is a decapeptide comprised of naturally occurring amino acids (which have the L-configuration except for the achiral amino acid glycine). Its sequence is as follows: (pyro) Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2. Many analogues of this natural material have been studied and the very large majority of them have proven to be of insufficient biological activity to be clinically useful. Certain select modifications have proven to have a beneficial effect on biological activity. By far the most significant modification is obtained by changing the 6-position residue from Gly to a D-amino acid. For example, replacing the Gly residue in the 6-position by D-Ala, D-Leu, D-Phe or D-Trp has led to a series of analogues of LH-RH with increased activity relative to LH-RH. See M. Monahan, et al, Biochem., 12, 4616 (1973) for [D-Ala.sup.6 ]LHRH; J. A. Vilchez-Martinez, et al, Biochem. Biophys. Res. Comm., 59, 1226 (1974) for [D-Leu.sup.6 ]LHRH and desGly.sup.10 [D-Leu.sup.6, Pro-NHEt.sup.9 ]LHRH; D. H. Coy, et al, J. Med. Chem., 19, 423 (1976) for [D-Phe.sup.6 ]LHRH; and W. Vale, et al, Clinical Endocrinology, 5th Supp., Blackwell Scientific Publications, Oxford, England (1976), p. 2615 and D. H. Coy, et al; Biochem. Biophys. Res. Comm., 67, 576 (1979) for [D-Trp.sup.6 ]LHRH.
In addition to the substantial increases in activity obtained by the above-referred to substitutions in position 6, further increases in activity may be obtained by removing the Gly-NH.sub.2 in position 10 and then producing a nonapeptide as an alkyl-, cycloalkyl- or fluoroalkylamide derivative or by replacing Gly-NH.sub.2 by an .alpha.-azaglycine amide. See for example, M. Fujino, et al, Biochem. Biophys. Res. Comm., 49, 863 (1972), D. H. Coy, et al, Biochem. 14, 1848 (1975) and A. S. Dutta, et al, J. Chem. Soc. Perkin I, 1979, 379.
Substitution of N-methyl-leucine for the leucine residue in position 7 leads to increased stability towards enzymatic degradation. See for example, N. Ling, et al, Biochem Biophys. Res. Comm., 63, 801 (1975).
Substitution of the tryptophan residue in position 3 by 3-(1-naphthyl)-L-alanine leads to an increase in biological potency. See for example, K. U. Prasad, et al, J. Med. Chem., 19, 492 (1976) and Y. Yabe, Chem. Pharm. Bull., 24 (12), 3149 (1976).
The tyrosine residue in position 5 can be replaced by phenylalanine or 3-(1-pentafluorophenyl)-L-alanine with the retention of substantial biological activity. See for example, N. Yanaihara, et al, Biochem. Biophys. Res. Comm., 52, 64 (1973), and D. Coy, et al, J. Med. Chem., 16, 877 (1973).
It would be desirable to prepare further analogues of LH-RH which have even a higher degree of biological activity than those heretofore described and which can be used clinically in animals and humans.